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Clinical Expert Series

Endometrial Cancer Joel I. Sorosky,

MD

The epidemiology, prevention, diagnosis, treatment, prognosis, and new International Federation of Gynecology and Obstetrics staging system of endometrial carcinoma are reviewed. Endometrial cancer has increased 21% in incidence since 2008, and the death rate has increased more than 100% over the past two decades. Precursor lesions of complex hyperplasia with atypia are associated with an endometrial carcinoma in more than 40% of cases. Endometrial cancer in white women occurs at twice the incidence as in black women, but, stage for stage, black women have a less favorable prognosis. Preoperative imaging cannot accurately assess lymph node involvement. Gross examination of depth of myometrial invasion does not have the sensitivity, specificity, positive predictive value, or negative predictive value to select women who can have lymphadenectomy safely omitted from the surgical procedure. Although surgical staging remains the most accurate method of determining the extent of disease, the therapeutic value of pelvic lymphadenectomy has not been established. The anatomical extent of lymphadenectomy and the number of lymph nodes removed to establish prognostic and therapeutic benefit are controversial. Research efforts are directed at identifying women with early stage endometrial cancer who only require total hysterectomy and bilateral salpingo-oophorectomy. Minimally invasive surgical techniques have become established as standard therapy for treating women with endometrial cancer. Women with a family history of hereditary nonpolyposis colorectal cancer are at increased risk for endometrial cancer. Conservative treatment to allow for childbearing is possible in select situations. Women with endometrial cancer should be managed by physicians experienced in the complex multimodality treatment of this disease. (Obstet Gynecol 2012;120:383–97) DOI: 10.1097/AOG.0b013e3182605bf1

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ndometrial cancer is the most common gynecologic malignancy in the United States and the fourth most common cancer in women after breast, lung, and colorectal cancers. The American Cancer Society estimates there will be 47,130 new cases and 8,010 deaths in 2012.1 The incidence of endometrial cancer has increased 21% since this topic was last reviewed in ObstetFrom the Department of Obstetrics and Gynecology, Hartford Hospital and the Hospital of Central Connecticut, The University of Connecticut, Hartford, Connecticut. Continuing medical education for this article is available at http://links.lww. com/AOG/A309. Corresponding author: Joel I. Sorosky, Department of Obstetrics and Gynecology, Hartford Hospital and the Hospital of Central Connecticut, The University of Connecticut, 80 Seymour Street, Hartford, CT 062102; e-mail: jsorosk@harthosp.org. Financial Disclosure The author did not report any potential conflicts of interest. Š 2012 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/12

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rics & Gynecology in 2008.2 The death rate per 100,000 population has increased more than 100% during the past 20 years and 8% since 2008. This is distressing given that overall death rates from cancer have decreased 1.6% per year in women, and these declines have been consistent since 2001.1 Ninety percent of women present with abnormal uterine bleeding and nearly 75% of women present with early stage disease. It is postulated that the increased death rate may be related to an increasing life span and coexisting medical comorbidities in these women. Women with an advanced stage diagnosed may have aggressive disease, denial of symptoms, genetic risk, confounding symptoms, or misdiagnosis. This review is directed toward the general obstetrician gynecologist. Emphasis is directed to scientific advances in this disease because this topic was last reviewed in Obstetrics & Gynecology in 2008. A new International Federation of Gynecology and Obstetrics (FIGO) staging system has been implemented and minimally invasive surgery has become accepted surgical therapy, but the roles of lymph node staging and

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postoperative adjuvant radiation therapy have become more controversial. The Ovid database was queried from 2007 through the first week of February 2012. The key words “endometrial neoplasms including diagnosis,” “epidemiology,” “genetics,” “pathology,” “prevention and control,” “radiotherapy,” “surgery,” and “therapy” were used to search for manuscripts in English. Sarcomas of the uterus are not discussed here. The mean age for endometrial adenocarcinoma is 61 years, with most cases diagnosed in women between the ages of 50 and 60 years.2 Ninety percent of cases occur in women older than 50 years. Endometroid is the most common histologic type. Approximately 20% of women have diagnoses before menopause and approximately 5% of women will have development of disease before age 40 years. Approximately 72% of endometrial cancers are stage I, 12% are stage II, 13% are stage III, and 3% are stage IV. Endometrial cancer commonly has been classified into three types (Table 1). Type I commonly is estrogen-related and occurs in younger, obese, or perimenopausal women. These tumors are usually low-grade and arise in a background of hyperplasia (Figs. 1 and 2). Type I disease represents the majority of endometrial cancers. Endometroid is the most common histology. These tumors may show microsatellite instability and mutations in PTEN, PIK3CA, K-ras, and CTNNBI.3 It has not been established with certainty whether obesity is behavioral, social, genetic, or an admixture. A genetic predisposition to obesity can increase the risk of endometrial cancer. Type II disease generally has high-grade tumors, is of serous or clear cell histology, occurs in an older cohort of women than type I, and is more common in black women (Figs. 3 and 4). These tumors may exhibit p-53 mutations in approximately 10 –30% of cases. Type II disease represents up to 10% of cases. The epidemiologic profile of women with type II disease is not certain.

Fig. 1. Endometroid adenocarcinoma (hematoxylin and eosin stain, 40⫻ magnification). Sorosky. Endometrial Cancer. Obstet Gynecol 2012.

Hereditary or genetic disease can have a familial association or can be part of the Lynch syndrome, hereditary nonpolyposis colorectal cancer. Genetic disease can represent up to 10% of cases, of which 5% are Lynch syndrome. A history should be taken from all women with endometrial cancer to determine if

Table 1. Classification of Endometrial Cancer Type I

Type II

Low-grade High-grade Minimal myometrial Deep myometrial invasion invasion Arising in a background Serous or clear-cell of hyperplasia Perimenopausal Estrogen-related Younger age Obesity

Familial Lynch

Reprinted from Sorosky JI. Endometrial cancer. Obstet Gynecol 2008;111:436 – 47.

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Fig. 2. Endometroid adenocarcinoma (hematoxylin and eosin stain, 400⫻ magnification). Sorosky. Endometrial Cancer. Obstet Gynecol 2012.

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RISK FACTORS

Fig. 3. Serous endometrial carcinoma (hematoxylin and eosin stain, 40⫻ magnification). Sorosky. Endometrial Cancer. Obstet Gynecol 2012.

there is a hereditary component. If the woman is at risk for hereditary disease, then she may be offered genetic counseling and consideration should be given for genetic testing. Other family members may be at risk for hereditary cancers and also may be candidates for genetic counseling.

Fig. 4. Serous endometrial carcinoma (hematoxylin and eosin stain, 400⫻ magnification). Sorosky. Endometrial Cancer. Obstet Gynecol 2012.

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The epidemiology of endometrial cancer includes women with genotypic and phenotypic risk. A recent prospective study reported that nearly 70% of women with early stage endometrial cancer were obese.4 This is greater than twice the percentage of previous reports.5 The relative risk (RR) for death increased with the body mass index (BMI, calculated as weight (kg)/[height (m)]2). For women with endometrial cancer and BMIs of 24 –30, the RR of death was 2.53, with BMIs of 35– 40 the RR was 2.77, and with BMIs more than 40 the RR of death increased to 6.25.6,7 Women who survived endometrial cancer had the highest rate of death when compared with other cancers. Women with endometrial cancer have other medical comorbidities that contribute to them dying from causes other than the cancer. Endometrial cancer survivors have unhealthy lifestyles that put them at risk for morbidity.8 After diagnosis and treatment, survivors should be offered muiltibehavorial lifestyle interventions. Another study also demonstrated that obese endometrial cancer patients had a higher mortality from medical comorbidities. Women with BMIs more than 40 had significantly shorter survival and experienced more endometrial cancer– unrelated deaths when compared with nonobese women.7 A single institution study of 442 women found BMI was also correlated to tumor grade, race, and stage at diagnosis.9 Reproductive, menstrual, and medical risk comorbidities can increase or decrease the risk of a woman having development of endometrial cancer.10 Continuous estrogen stimulation, albeit it exogenous or endogenous, can alter the normal endometrial cycle. Anovulation results in continuous unopposed estrogen stimulation because there is no corpus luteum to produce progesterone. Anovulation is common during perimenopause. Obesity, generally more than 50 pounds over ideal body weight, can result in endogenous estrogen because of peripheral conversion of androstenedione into estrone. Women with BMIs more than 30 have two times to three times the risk of development of endometrial cancer. Data from observational studies report that both symptomatic vaginal bleeding and postmenopausal status in women with endometrial polyps are associated with an increased risk of endometrial cancer.11 Estrogen-producing tumors, unopposed estrogen therapy, cirrhosis, and tamoxifen also may result in excess estrogen stimulation to the endometrium. Although tamoxifen is an antiestrogen in breast tissue, it can have estrogenic activity in the endometrium.12 Unopposed estrogen replacement in menopause is

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associated with a fourfold to eightfold increased risk of disease, whereas estrogen and progesterone replacement therapy in the menopause decreases the risk of disease. The extent of reduction of cancer risk with progestin is based on the type of progestin administered, dosage, and duration of use. Progestincontaining or combination oral contraceptives decrease the risk of disease by approximately 50%.13 Nulliparity and diabetes are associated with a twofold to threefold increased incidence of disease, whereas hypertension appears to be related to obesity and diabetes and is not an independent risk factor. Nulliparity is believed to be related to infertility rather than intentional prevention of pregnancy. Infertility related to anovulation and progesterone deficiency increase the risk as opposed to infertility related to tubal factors. The incidence of endometrial cancer in white women is twice the incidence of that of black women.14,15 Stage for stage, black women have a less favorable prognosis. It is unclear if this survival disadvantage for black women is related to tumor aggressiveness, effectiveness of treatment, differences in the extent of disease within similar stages, or biologic variation by race. More research is needed to clarify these racial disparities. Tamoxifen, when used for chemoprevention of breast cancer, increased the risk of endometrial cancer nearly threefold. Whereas the majority of tamoxifen-induced carcinomas were endometroid in histology, low-grade, and staged, there are reports of tamoxifen-associated high-grade tumors and sarcomas. Women with a history of tamoxifen therapy should have continued surveillance after completion of tamoxifen to allow for early diagnosis of uterine cancer. In one study of 106 women, nearly 40% of women who had development of uterine cancer after tamoxifen therapy did so more than 12 months after discontinuation with a median time of 33 months.12,16,17 Screening asymptomatic women using tamoxifen with ultrasonography or endometrial biopsy is not recommended. These women should be educated about reported symptoms of increased vaginal discharge or bleeding to their physician. Symptomatic women should undergo evaluation for endometrial cancer or its precursors. Oral estrogen replacement is associated with a 2-fold to 12-fold increased risk of endometrial cancer. Increasing dosage and duration of use are associated with increased risk. This risk continues until 2 to 3 years after cessation of estrogen therapy. Tumors associated with estrogen use are usually early stage at diagnosis and of lower grade.18 These tumors generally arise in a background of hyperplasia.

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The majority of cases of endometrial adenocarcinoma results from estrogenic stimulation with complex hyperplasia with atypia or endometrial intraepithelial neoplasia as a precursor lesion. Approximately 10% of endometrial adenocarcinoma is not related to estrogen excess, that is, type II. These tumors tend to occur at an older age than estrogen-associated lesions and are poorly differentiated with serous or clear-cell histology. Uterine papillary serous carcinoma is an aggressive tumor that histologically resembles papillary serous ovarian carcinoma. There are no risk factors, as opposed to type 1 disease. Serous carcinoma of the endometrium is more commonly seen in older women and in black women. Clear-cell uterine adenocarcinoma also is an aggressive tumor that is histologically similar to clear-cell adenocarcinoma that is seen in the ovary or cervix.

ENDOMETRIAL HYPERPLASIA Women with endometrial hyperplasia are usually identified during evaluation of menometrorrhagia or postmenopausal bleeding. Diagnosis is made by histologic evaluation of the endometrium. From 1985 until 2006, it was believed that complex hyperplasia with atypia had a 29% likelihood of progressing to endometrial cancer, whereas simple hyperplasia with or without atypia and complex hyperplasia without atypia had a small incidence of progression to cancer.19 This retrospective study had a small number of patients. Medical therapy with progestins was recommended for women with simple hyperplasia with or without atypia and complex hyperplasia without atypia diagnosed. Hysterectomy was recommended for those women with complex hyperplasia with atypia. Medical therapy with progestins was recommended in instances when future childbearing was desired. The Gynecologic Oncology Group (GOG) sought to validate the reproducibility of the referring institution’s pathologic diagnosis of complex hyperplasia with atypia (atypical endometrial hyperplasia) in a multiinstitutional prospective manner.20 In the studies cited, complex hyperplasia with atypia and atypical endometrial hyperplasia are used interchangeably. A panel of three pathologists independently reviewed the specimens from 306 women with the diagnosis based on either endometrial biopsy or curettage. These women underwent hysterectomy within 12 weeks of biopsy diagnosis of atypical endometrial hyperplasia. The referring institution’s pathologist’s diagnosis of atypical endometrial hyperplasia was supported by the majority of the panel in only 38% of cases. The majority diagnosis was adenocarcinoma in 29% of cases, cycling endometrium in 7%, and hyperplasia without atypia in 18% of

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cases. Unanimous agreement for any diagnosis was reached among all three pathologists in only 40% of cases. Reproducibility of the referring institution’s pathologist’s diagnosis of atypical endometrial hyperplasia by a panel of gynecologic pathologists was poor. Both underestimation and overestimation of the severity of the lesion were very common. The level of reproducibility among the three reference pathologists also was poor. Better criteria and better sampling are needed to improve reproducibility of atypical endometrial hyperplasia if this diagnosis is to be used for clinical decisions. Given that the reproducibility of the diagnosis of atypical endometrial hyperplasia on permanent section is poor, clinical decisions based on a frozen-section diagnosis of atypical endometrial hyperplasia would be similar if not less reproducible. The use of intraoperative frozen-section diagnosis is not recommended. In a multi-institutional prospective study, GOG also estimated the prevalence of concurrent carcinoma in women with a referring institution’s pathologic diagnosis of atypical endometrial hyperplasia.21 A panel of three pathologists independently reviewed the specimens from 306 women with the diagnosis based on either endometrial biopsy or curettage. These women underwent hysterectomy within 12 weeks of biopsy diagnosis of atypical endometrial hyperplasia. Of 289 specimens that met inclusion criteria, the study panel review found 25.6% were diagnosed as less than atypical endometrial hyperplasia, 39.8% were diagnosed as atypical endometrial hyperplasia, and 29.1% (independent of the review of the previous biopsy specimen) were diagnosed as endometrial cancer. In 5.5% there was no consensus on the diagnosis. The overall rate of endometrial carcinoma was 42.6% (including biopsy specimen and hysterectomy specimen, 123 of 289 specimens). Of these, 30.9% (38 of 123 specimens) had myometrial invasion and 10.6% (13 of 123 specimens) had invasion to the outer half of the myometrium. Among the women who had hysterectomy specimens with carcinoma, 14 of 74 women (18.9%) had a study panel consensus diagnosis of less than atypical endometrial hyperplasia and 54 of 84 women (64.3%) had a study consensus diagnosis of carcinoma. Among women who had no consensus in their biopsy diagnosis, 10 of 16 women (62.5%) had carcinoma in their hysterectomy specimens. These authors concluded that the prevalence of endometrial carcinoma in women with a community hospital biopsy diagnosis of atypical endometrial hyperplasia was high (42.6%). Clinicians and patients should acknowledge the high rate of concurrent carcinoma of more than 40% when planning therapy for atypical endometrial hyperplasia.

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In a population-based retrospective cohort study of 824 women within a large health maintenance organization, dilation and curettage (D&C) performed after a biopsy-proven diagnosis of complex atypical hyperplasia lowered the rate of unexpected cancer compared with biopsy alone.22 Overall, 48% of women with complex atypical hyperplasia were found to have cancer. Preoperative D&C was associated with a statistically significant decrease in the risk of having cancer found at surgery when compared with at biopsy alone. Although 18% of women still had an invasive endometrial carcinoma at hysterectomy, D&C is recommended to reduce the incidence of unanticipated cancer in the final hysterectomy specimen. This could allow for triage and evaluation of cancer before definitive surgery. In this study, the risk of unexpected cancer was strongly related to age. Given the incidence of more than 50% myometrial invasion in women with a preoperative diagnosis of atypical endometrial hyperplasia and an overall 42.6% incidence of malignancy, a preoperative gynecologic oncologic consultation may be prudent in women with atypical endometrial hyperplasia until the criteria for reproducibility of atypical endometrial hyperplasia and distinction from invasive carcinoma are improved. Women with simple and complex hyperplasia without atypia and those with simple hyperplasia with atypia may be treated with progestins because the risk of endometrial carcinoma is low. Common regimens include cyclic medoxyprogesterone 10 mg daily for 14 days per month or continuous megesterol acetate 20 – 40 mg daily. Alternatively, a progestin-releasing intrauterine device has been reported to be effective in treating hyperplasia.23 Women with complex hyperplasia with atypia have a more than 40% incidence of a coexistent adenocarcinoma. Hysterectomy is the treatment of choice for complex hyperplasia with atypia. For those individuals with atypical endometrial hyperplasia desiring childbearing or those with medical comorbidities that preclude surgery, treatment with progestins to allow for subsequent pregnancy has been reported.24 The endometrium should be evaluated within 3– 4 month. After childbearing is completed in women with complex hyperplasia with atypia, hysterectomy is recommended. A retrospective cohort study of 1,443 women in an integrated health plan with endometrial complex atypical hyperplasia compared those prescribed progestin with those not prescribed progestin.25 The risk of endometrial carcinoma was decreased threefold to fivefold in women with complex or atypical endometrial hyperplasia diagnosed and who were adminis-

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tered progestin. The hysterectomy risk was also decreased. Complex endometrial hyperplasia with atypia should be treated with hysterectomy if possible because of the high incidence of progression to cancer and the inability of endometrial biopsy and D&C to reliably exclude cancer. This study suggested that among women who did not have a hysterectomy or a diagnosis of endometrial carcinoma treated with progestin, the risk of endometrial carcinoma was lower than in those women not treated with progestin. The majority of these women had carcinoma diagnosed in the year after their diagnosis of atypical hyperplasia. None of these women died from disease complications. This large study provides additional validation that progestin therapy may be used to treat atypical endometrial hyperplasia in the short-term in selected women. This study was not able to address the long-term response to ongoing progestin therapy. Endometrial intraepithelial neoplasia is an alternative classification designed to replace the hyperplasia terminology. Endometrial intraepithelial neoplasia is a precursor to endometrial adenocarcinoma that is characterized by a distinctive histologic appearance (Fig. 5) and a monoclonal growth of mutated cells.26 Application of molecular standards and computeraided morphometric criteria for the diagnosis of endometrial intraepithelial neoplasia may be more reproducible than the visual diagnosis of complex hyperplasia with atypia.27 Currently, this terminology

Fig. 5. Endometrial intraepithelial neoplasia (hematoxylin and eosin stain, 400⍝ magnification). Sorosky. Endometrial Cancer. Obstet Gynecol 2012.

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is not widely used. If the endometrial intraepithelial neoplasia terminology is widely adopted by the pathology community, then this diagnosis may be more useful for clinical decisions than the current classification system for hyperplasia.

DIAGNOSIS OF ENDOMETRIAL CANCER Abnormal uterine bleeding including postmenopausal bleeding, menorrhagia, or metrorrhagia are the most common presenting symptoms for women with endometrial hyperplasia or carcinoma. Atypical glandular cells on cytologic screening should be evaluated with colposcopy and endocervical curettage and an endometrial biopsy in women older than age 35 years or those with risk factors for endometrial cancer.28,29 Endometrial sampling should be recommended in women older than 40 years with abnormal bleeding or in younger women with risk factors for disease. A D&C should be performed if complex hyperplasia with atypia is detected because of the high incidence of a coexistent carcinoma. Hysteroscopy is generally reserved for those women who continue to have symptoms that cannot be explained by office biopsy. Hysteroscopy is better than curettage at detecting polyps and submucosal leiomyomas. Based on data from observational studies, both symptomatic vaginal bleeding and postmenopausal status in women with endometrial polyps are associated with an increased risk of endometrial cancer.11 Whereas sonohysterography also can detect these lesions, a tissue diagnosis may be warranted depending on the clinical context (Figs. 1 and 2). The use of hysteroscopy for evaluation of abnormal bleeding is common. When endometrial cancer is diagnosed after hysteroscopy sampling of the peritoneal fluid during standard cancer staging, surgery has sometimes led to positive cytologic findings. The clinical significance of malignant cytology and the potential for tumor dissemination after hysteroscopic after diagnosis of endometrial cancer is uncertain. A search of the Cochrane Central Trials Registry, the Web of Science, and PubMed for publications about the role of hysteroscopy, laparoscopy, and saline infusion ultrasonography on dissemination of endometrial cancer cells and the prognostic significance of positive peritoneal washings found no evidence for altered prognosis when these procedures were used to diagnose endometrial cancer.30 Another meta-analysis of 19 studies including 1,099 women with endometrial cancer who underwent preoperative hysteroscopy demonstrated that hysteroscopy resulted in a statistically higher rate of positive peritoneal cytology but found no evidence to support an association

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between preoperative hysteroscopy and a worse prognosis.31 This supports the FIGO decision in 2009 to omit malignant peritoneal cytology (Table 2) from staging.32 Most gynecologic oncologists plan treatment according to other risk factors, including myometrial invasion, grade, histology, serosal involvement, extrauterine disease, and nodal status. Several studies have evaluated the effectiveness of transvaginal ultrasonography in diagnosing or screening for endometrial cancer in menopausal women. In a study of 448 women, an endometrial thickness less than 5 mm had a negative predictive value of 99%.33 In 100 menopausal women, an endometrial stripe of less than 4 mm had a 100% negative predictive value.34 Another study found that 96% of women with carcinoma had an endometrial thickness more than 5 mm.35 The use of transvaginal ultrasonography does not replace a tissue diagnosis but may be a useful adjunct in medically compromised women. Persistent vaginal bleeding must be evaluated regardless of ultrasonographic findings. Based on data from observational studies, both symptomatic vaginal bleeding and postmenopausal status in women with Table 2. Revised 2009 International Federation of Gynecology and Obstetrics Staging of Endometrial Cancer Stage I IA IB II III IIIA IIIB IIIC IIIC1 IIIC2 IV IVA IVB

Description Tumor confined to uterine corpus No or less than half myometrial invasion Invasion to or in more than half of the myometrium Tumor invades the cervical stroma but does not extend beyond the uterus Local or regional spread of the tumor Tumor invades the serosa or adnexae or serosa and adnexae Vaginal or parametrial involvement Metastases to the pelvic or paraarotic or pelvic and paraaortic lymph nodes Positive pelvic nodes Positive paraaortic lymph nodes with or without positive pelvic nodes Tumor invades bladder or bowel mucosa or distant metastases Tumor invasion of bladder or bowel or bladder and bowel mucosa Distant metastasis, including intraabdominal metastases, inguinal lymph nodes, or intraabdominal metastases and inguinal lymph nodes

The stage also includes the grade of the tumor. Grade 1, 5% or less of the tumor is solid; grade 2, 6 –50% of the tumor is solid; grade 3, more than 50% of the tumor is solid. Modified from Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynecol Obstet 2009;105:103– 4, with permission from Elsevier.

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endometrial polyps are associated with an increased risk of endometrial cancer.11

PREOPERATIVE EVALUATION OF ENDOMETRIAL CANCER In addition to age-associated preoperative blood and electrocardiogram studies, women with a diagnosis of endometrial cancer and suspected metastatic disease may have a preoperative CA 125 test. Sood et al36 reported that elevated CA 125 levels have been reported to be the single most significant predictor of extrauterine disease. It is common for women with endometrial cancer to have comorbidities such as obesity, hypertension, coronary artery disease, or pulmonary disease. Preoperative risk assessment is important to optimize therapy of concurrent medical comorbidities. These women are at increased risk for venous thromboembolic disease and prophylaxis should be used. Routine computed tomography scan and magnetic resonance imaging (MRI) rarely alter management and are poor predictors of nodal disease.37 However, MRI is better at determining myometrial invasion than computed tomography.38 Neither computed tomography nor MRI is recommended for routine preoperative evaluation. Screening for age-appropriate and risk-appropriate cancers should be performed. If age-appropriate, then mammography and colonoscopy should be performed before surgery. However, MRI for evaluating the depth of myometrial invasion preoperatively does not have the sensitivity, positive predictive value, or accuracy to make clinical decisions.39 Although MRI has been demonstrated to have a negative predictive value, the probability of the absence of myometrial invasion is approximately 40%. Also, MRI should not be used to determine which women should and should not have lymphadenectomy. In endometrial cancer, up to 50% of lymph node metastases are smaller than 1 cm in diameter. Fludeoxyglucose (18F)-positron emission tomography was found to be only moderately sensitive in predicting lymph node metastasis in women with endometrial cancer.40 Preoperative evaluation with this test cannot replace pelvic lymphadenectomy. According to the 2005 American College of Obstetricians and Gynecologists Practice Bulletin, Management of Endometrial Cancer, when practical and feasible, preoperative consultation with a physician with advanced training and demonstrated competence such as a gynecologic oncologist may be recommended.

SURGERY FOR ENDOMETRIAL CANCER Total hysterectomy with bilateral salpingo-oophorectomy is the primary treatment for women with endo-

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metrial carcinoma. Approximately 75% of women will have stage I disease curable by surgery alone. Those with more advanced disease may require chemotherapy or radiation therapy. Complete surgical staging includes total hysterectomy with bilateral salpingo-oophorectomy and pelvic and paraaortic lymphadenectomy. Pelvic washings are no longer part of FIGO staging but may be reported separately. Surgical staging allows for the most accurate assessment of extent of disease. The FIGO staging has been surgical since 1988. Surgical staging provides prognostic and uncertain therapeutic benefits to women with endometrial cancer. Some authors have reported pelvic and paraaortic lymphadenectomy to be associated with improved survival.41– 44 Two large randomized European trials have reported that lymphadenectomy had no effect on survival for women with early stage endometrial cancer.45,46 Whereas critics of these two studies have suggested methodologic concerns, many women with endometrial cancer do not undergo lymph node staging.47 There is absolutely no consensus regarding which patients require lymph node staging or what constitutes an adequate lymphadenectomy in terms of number of nodes removed and extent of lymphadenectomy. Surgical therapy may be via laparotomy, laparoscopic-assisted vaginal hysterectomy, total laparoscopic hysterectomy, or robotic total hysterectomy with pelvic and paraaortic lymphadenectomy.48 Vaginal hysterectomy with bilateral salpingo-oophorectomy is occasionally recommended in women with medical comorbidities that preclude abdominal or laparoscopic procedures. Primary radiation therapy is an option for the medically inoperable.49 The GOG, in the LAP2 study, demonstrated that laparoscopic surgical staging for endometrial cancer is feasible and safe in terms of short-term outcomes and results in fewer complications and shorter hospital stay.50 Despite a 26% conversion to laparotomy rate, there was a short-term quality-of-life benefit demonstrated at 6 weeks in the laparoscopy arm that disappeared by 6 months. A follow-up study demonstrated the estimated 5-year overall survival was almost identical in both arms at 89.8%.51 When robotic-assisted hysterectomy for endometrial cancer was compared with traditional laparoscopic and laparotomy approaches, perioperative clinical outcomes for robotic and laparoscopic hysterectomy appeared similar, with the exception of less blood loss for robotic cases and longer operative times for robotic and laparoscopy cases.52 These studies have demonstrated that minimally invasive surgery is equivalent to traditional laparotomy in terms of adequacy of surgical resection and lymph node counts with decreased postoperative

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complications, shorter hospital stay, and improved short-term quality of life. Long-term outcomes of women undergoing minimally invasive surgery for endometrial cancer are not available. The cost benefit among the minimally invasive procedures is controversial.53 Most gynecologic oncologists recommend minimally invasive surgery for endometrial cancer when appropriate and feasible. Before the 2005 American College of Obstetricians and Gynecologists Practice Bulletin, Management of Endometrial Cancer, which was reaffirmed in 2011, the treatment of endometrial cancer had been controversial with respect to whether an individual with subspecialty training in gynecologic oncology performed the surgery, the indications for lymphadenectomy, and the route of surgery (laparoscopic compared with open). The recommendations in 2005 clarified many of these issues. Pelvic and paraarotic lymphadenectomy were recommended to accurately stage endometrial cancer. Preoperative imaging cannot accurately assess lymph node involvement. Approximately 50% of lymph node metastases in endometrial cancer are less than 1 cm in diameter. Visualization and palpation of retroperitoneal lymph nodes cannot accurately predict the presence of metastasis. Gross examination of depth of myometrial invasion does not have the sensitivity, specificity, positive predictive value, or negative predictive value to select women who can have lymphadenectomy safely omitted from the surgical procedure. In the absence of ideal noninvasive preoperative testing, surgical staging remains the most accurate method of determining the extent of disease.54 There has been controversy regarding whether to surgically stage grade 1 endometrial adenocarcinoma in women. In a study of 181 women with grade 1 endometrial carcinoma, 82% underwent surgical staging. In women who have undergone staging, 3.2% had complications. Nineteen percent of cases were histologically upgraded. Lymph node involvement was present in 4.4% of women. High-risk uterine features including more than 50% myometrial invasion, grade 3 histology (despite a preoperative grade 1 diagnosis), high-risk histologic variants, and cervical involvement were found in 26% of women. Overall, surgical staging in women presenting with grade 1 disease significantly affected postoperative treatment decisions in 29% of women. Omitting lymphadenectomy in women presenting with grade 1 disease may lead to inappropriate postoperative treatment.55 Pelvic and paraaortic lymph node sampling are useful in surgical staging to provide accurate prognostic evaluation. A therapeutic role for lymphadenec-

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tomy is not universally accepted. A randomized trial to evaluate therapeutic lymphadenectomy in endometrial cancer was performed by the Medical Research Council in England.56 The study found no therapeutic benefit for the procedure. This study has been criticized because paraaortic lymph node dissection was not mandated and postoperative adjuvant radiation therapy was not directed by the nodal status. Research efforts are ongoing to identify a subset of women who may not require surgical staging.57 No specific criteria exist for management of women who have undergone total hysterectomy with bilateral salpingo-oophorectomy without lymphadenectomy for initial treatment of endometrial cancer. A recent study of Surveillance, Epidemiology, and End Results data revealed that approximately 62% of women (24,436 of 39,396) underwent hysterectomy for endometrial cancer without lymphadenectomy.58 Using data retrospectively reviewed from GOG in the LAP2 study, criteria were used to aid in treatment planning for reoperation in women who did not undergo complete surgical staging for endometroid adenocarcinoma.59 Women at low risk with tumor size of 2 cm or less, grade 1 or 2 disease, and myometrial invasion of 50% or less were found to have a rate of nodal metastasis of only 0.8%. Serous and clear-cell endometrial carcinoma can arise in a background of an atrophic endometrium. The precursor lesion is considered to be endometrial intraepithelial carcinoma rather than hyperplasia. Serous carcinoma can be multifocal and distant disease may be detected in the absence of myometrial invasion. Comprehensive surgical staging similar to ovarian carcinoma should be performed. Omentectomy along with peritoneal and upper abdominal biopsies are recommended. Women with advanced stage disease may benefit from removal of the bulk disease.60 Maximal surgical effort should be directed at these women. A metaanalysis of 14 retrospective cohorts including 672 women with advanced or recurrent endometrial cancer undergoing complete surgical cytoreduction or adjuvant radiation or receiving adjuvant chemotherapy demonstrated that complete cytoreduction to no gross disease was associated with superior overall survival.61 The route of primary surgery, the value and extent of lymphadenectomy, and the value of postoperative adjuvant radiation therapy are now very controversial. Most cases of endometrial cancer are cured after total hysterectomy with bilateral salpingo-oophorectomy. Also controversial is the role of the general obstetrician gynecologist in the management of endometrial cancer. In a study of 6,015 women

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undergoing abdominal hysterectomy for endometrial cancer between 2003 and 2007, perioperative surgical complications, medical complications, and intensive care unit requirements were lower for women treated by high-volume (more than 30 procedures per year) surgeons.62 Two studies demonstrated that primary management by a gynecologic oncologist resulted in an efficient use of health care resources and minimized potential morbidity.63,64 Women with complex hyperplasia with atypia have a 40% incidence of a coexistent endometrial adenocarcinoma. The role of the gynecologic oncologist in caring for these women is unclear. Preoperative consultation with a gynecologic oncologist is recommended for women with a known endometrial cancer, for women with an endometrial cancer diagnosed unexpectedly at hysterectomy, and for women with advanced stage disease.

ADJUVANT RADIATION THERAPY No adjuvant therapy is recommended for women with surgical staging indicating low risk for recurrence. Radiation therapy traditionally had been recommended as adjuvant therapy for women at risk for recurrence. Several randomized trails have failed to demonstrate a survival advantage for adjuvant whole pelvic radiation therapy for stage I disease.65,66 All women in the GOG study underwent surgical staging and then were randomized to radiation therapy or observation.43 The Post Operative Radiation Therapy in Endometrial Carcinoma study determined the value of radiation therapy in women after surgical therapy without comprehensive surgical staging.44 Although local control was better in the treatment arm, there was no difference in survival. In the GOG study, a subgroup of patients at high intermediate risk was defined as those with: 1) moderate to poorly differentiated tumor, presence of lymphovascular invasion, and outer one third myometrial invasion; 2) age 50 years or older with any two risk factors listed here; or 3) age of at least 70 years with any risk factor listed here. All other eligible participants were considered to be in a subgroup at low intermediate risk. The GOG study concluded that adjunctive radiation therapy in early-stage intermediate-risk endometrial carcinoma decreases the risk of recurrence but should be limited to patients whose risk factors fit a high intermediate risk definition. Between July 1996 and March 2005, 905 women from seven countries including the United States with intermediate-risk or highrisk early stage disease were randomized to observation or to external beam radiation therapy.56 There was no evidence that overall survival with external beam radiation therapy was better than with observa-

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tion. The study concluded that adjuvant external beam radiation therapy could not be recommended as routine treatment for women with intermediate-risk or high-risk early stage endometrial cancer with the aim of improving survival. The absolute benefit of external beam radiation therapy in preventing isolated local recurrence was small and was not without toxicity. A survey of members of the Society of Gynecologic Oncologists in 2005 queried the practice of surgical staging and adjuvant radiation therapy.67 Society of Gynecologic Oncologists members were more likely to perform complete surgical staging during all surgeries for endometrial cancer in 2005 than in 1999 (71% compared with 48%; P�.001). A higher percentage of respondents described surgery as a complete lymphadenectomy (76% compared with 44%; P�.001) and believed this was therapeutic (71% compared with 66%; P⍽.04). Approximately half of Society of Gynecologic Oncologists members used laparoscopic-assisted staging in the primary treatment of endometrial cancer. Since 1999, there has a significant decrease in the recommendation for postoperative radiation therapy. In almost all cases in which radiation therapy was recommended, the use of vaginal brachytherapy was more common than pelvic radiation therapy. In all situations, consultation recommendations for additional intervention were more likely if complete surgical staging had not been performed, suggesting that all patients with endometrial cancer would benefit from surgery by a gynecologic oncologist. Twelve years of experience, from 1993 to 2004, at Memorial Sloan-Kettering Cancer Center showed an increase in surgical staging and a decrease in the use of postoperative radiation therapy.68 When surgical therapy of endometrial cancer has included lymphadenectomy, there has been a decrease in the use of adjuvant radiation therapy without any decrease in survival.

Postoperative Therapy Vaginal brachytherapy can reduce the incidence of vaginal vault recurrence. Using high-dose therapy, treatment can be on an outpatient basis with low morbidity. There has been a single institution study reporting a postoperative survival advantage of brachytherapy.69 Recommendations for brachytherapy are currently undergoing investigation. The GOG is currently studying treatment between external beam pelvic radiation therapy and vaginal brachytherapy with three cycles of paclitaxel and carboplatin for women with stage I disease and intermediate-risk or high-risk features (GOG study 249).

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FAMILIAL ENDOMETRIAL CANCER There are numerous reports describing family history as a risk factor for endometrial cancer. Women with a family history of colon cancer are at increased risk. Hereditary nonpolyposis colorectal cancer, Lynch syndrome, is an autosomal-dominant condition, with endometrial cancer being the most common cancer seen in association with hereditary nonpolyposis colorectal cancer.70 Other malignancies associated with hereditary nonpolyposis colorectal cancer can occur in the brain and gastric, biliary, intestinal, ovarian, and urinary tracts. Hereditary nonpolyposis colorectal cancer is associated with germline mutations in any one of six genes, PMS2 on chromosome 7, MLH1 on chromosome 3, and MSH6, MSH2, or PMS1 on chromosome 2. Mismatch repair failure leads to microsatellite instability. Hereditary nonpolyposis colorectal cancer increases the population risk of endometrial cancer from 0.2% to 20% by age 50 and from 1.5% to 60% by age 70. The lifetime risk for hereditary nonpolyposis colorectal cancer gene carriers can be as high as 30%. Endometrial cancers in Lynch syndrome can be of any grade or histology. Up to 35% of endometrial cancers in this syndrome may be of high stage or adverse histology. Many women with endometrial cancer diagnosed will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. Of 61 consecutive pathology specimens in women with endometrial cancer younger than age 50 years, 34% of the tumors had absence of at least one of the four mismatch repair proteins.71 Women with endometrial cancer diagnosed before age 50 years should be considered for immunohistochemical testing. There are some authors who advocate this testing for all women with endometrial cancer. Obese women were less likely than nonobese to have a mismatch repair deficiency. Because these women can have development of colon cancer before age 50 years and because disease may be commonly found in the proximal colon, colonoscopy should be started every other year beginning at age 20 years and should be performed annually after age 35 years. Endometrial screening including transvaginal ultrasonography, CA 125 examinations, and pelvic examination should commence at age 30. Endometrial biopsy should be performed if symptoms of irregular bleeding or menorrhagia develop. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has been proposed as an effective strategy for preventing endometrial and ovarian cancer in women with Lynch syndrome as a risk-reducing procedure after childbearing is completed.72

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Most studies do not suggest that the BRCA1 or BRCA2 gene is associated with endometroid endometrial cancer. Several reports suggest that the papillary serous histologic subtype of endometrial cancer may be linked to BRCA mutations. There are several studies suggesting removing the uterus for prophylaxis in BRCA1-positove and BRCA2-positive women undergoing prophylactic salpingo-oophorectomy for ovarian cancer prevention to prevent serous papillary uterine cancer.73–75 Although controversy exists, this information should be discussed with women contemplating prophylactic risk-reducing surgery for BRCA mutations. Hysterectomy at the time of prophylactic bilateral salpingo-oophorectomy in BRCA carriers is not universally recommended.

endometrial cancer. Endometrial sampling should be performed only in symptomatic women.

Screening

Treatment of recurrent disease depends on the original stage, the location of the recurrence, and previous treatments. The most common site for recurrence for stage I disease is the vagina.65,81 Isolated vaginal recurrences in women who did not undergo radiation therapy are generally treated with whole pelvic radiation therapy and vaginal brachytherapy. The Post Operative Radiation Therapy in Endometrial Carcinoma trial reported survival after relapse was significantly better in the patient group without previous radiation therapy.81 Treatment for vaginal relapse was effective, with 89% complete response and 65% 5-year survival in the control group. The excellent survival after treatment for vaginal relapse is among the reasons that adjuvant radiation therapy has not yielded a survival advantage. There was no difference in survival between patients with pelvic relapse and those with distant metastases. If the recurrence is limited to the vagina, then survival is better than it would be if the disease involved the pelvic sidewall. A multi-institutional retrospective review from the United States found similar results.82 Eighty-one percent of isolated vaginal recurrences were salvaged with radiation therapy. The mean time to recurrence was 24 months, and the mean follow-up was 63 months. Among women, 18% died from subsequent recurrent disease. The 5-year overall survival was 75%. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy, further questioning the role of adjuvant therapy for patients with uterine-confined endometrial cancer at the time of initial diagnosis. For systemic disease, hormonal therapy with progestins has been a favored therapeutic option because of its minimal toxicity. The response rates have been

Screening has not been found to be effective in diagnosing endometrial cancer in asymptomatic women, and no screening criteria have been established except those for women with Lynch II syndrome. Guidelines from the Bethesda system recommend that normal endometrial cells be reported in women age 40 and older. A study of 29,114 asymptomatic postmenopausal women with normal endometrial cells on routine screening cytology reported a prevalence rate of premalignant disease of 6.5% compared with a rate of 0.2% in those without disease.76 In a study of asymptomatic women with normal endometrial cells on liquid-based cytology, 2.1% had endometrial pathology.77 Because approximately 50% of women with endometrial cancer have malignant cells on screening cytology, cervical cytology is not a useful screening test. Several studies have demonstrated that women with malignant cells in routine cytology are more likely to have more advanced disease than those without malignant cytology. Malignant cytology is not an established independent prognostic variable. Although evidence-based data are lacking, screening may be considered in women at increased risk, such as postmenopausal women using estrogen therapy without progestin and premenopausal women with anovulatory cycles. In women with a genetic predisposition or using tamoxifen, increased awareness of the signs and symptoms of endometrial cancer may allow for early detection. In woman using tamoxifen for breast cancer prevention, transvaginal ultrasonography is associated with a high false-positive rate because tamoxifen also induces subendometrial cyst formation. Endometrial biopsy samples from asymptomatic woman had low yields.78 Woman using tamoxifen should be counseled about the signs and symptoms of

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Follow-Up Most endometrial cancers recur within the first 2 years after treatment. Women should undergo examination every 3– 4 months for the first 2 years, every 6 months for the next 3 years, and yearly after 5 years. It is unclear if annual chest radiographs contribute to early detection of recurrence. It is uncertain whether vaginal cytology contributes to early detection of recurrence because most lesions detected by cytology have been visually apparent. Most recurrences are detected when diagnostic testing is dictated by symptoms.79,80

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reported in 10 –25% of women. Recent studies have tried to improve this response rate with combined therapy with tamoxifen to increase the progesterone receptor expression and medroxyprogesterone acetate.83 The response rate was 33%. The median progression-free survival was 3 months and median overall survival was 13 months. The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Outcomes are better with chemotherapy, and chemotherapy is now used as the primary therapy for advanced and metastatic disease. Chemotherapy can be initial therapy for advanced disease or used for recurrence after hormonal therapy. The combination of cisplatin, doxorubicin, and paclitaxel is the most active chemotherapeutic regimen reported in advanced or recurrent endometrial cancer. The GOG performed a randomized prospective study of cisplatin, doxorubicin, and paclitaxel compared with cisplatin and doxorubicin.84 Objective response (57% compared with 34%; P⬍.01), progression-free survival (median, 8.3 compared with 5.3 months; P⬍.01), and overall survival (median, 15.3 compared with12.3 months; P⫽.037) were improved with cisplatin, doxorubicin, and paclitaxel. Treatment was hematologically well-tolerated, with only 2% of patients receiving cisplatin and doxorubicin and 3% of patients receiving cisplatin, doxorubicin, and paclitaxel experiencing neutropenic fever. Neurologic toxicity was worse for those receiving cisplatin, doxorubicin, and paclitaxel, with 12% with grade 3 and 27% with grade 2 peripheral neuropathy compared with 1% and 4%, respectively, in those receiving cisplatin and doxorubicin. Patientreported neurotoxicity was significantly higher in the cisplatin, doxorubicin, and paclitaxel arm after two cycles of therapy. Cisplatin, doxorubicin, and paclitaxel significantly improved RR, progression-free survival, and overall survival compared with cisplatin and doxorubicin. Although cisplatin, doxorubicin, and paclitaxel is the most active regimen, the toxicity has led many physicians to treat women with carboplatin and paclitaxel. At the 2012 Society of Gynecology Oncology Annual Meeting on Women’s Cancer, an oral abstract reviewed these data and established noninferiority of cisplatin and doxorubicin compared with cisplatin, doxorubicin, and paclitaxel.

Prognosis Stage is the most important prognostic factor, and surgical staging offers the most accurate prognostic information. Surgical staging facilitates adjuvant ther-

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apeutic recommendations. Because a new FIGO staging system was implemented in 2009, prospective data for survival are not available.32 Cases of stage IA and IB were combined into a single stage, stage IA. Cervical glandular involvement was omitted from the criteria for staging and only those women with cervical stromal invasion are now classified as having stage II. Peritoneal cytology has been removed as criteria for staging. Women with nodal metastasis are now stratified into the same category as those with pelvic nodal disease IIIC1 and those with paraaortic nodal disease IIIC2. A population-based analysis was performed comparing the performance of the 1988 and 2009 FIGO staging systems in women with endometroid adenocarcinoma treated between 1988 and 2006 and was recorded in the Surveillance, Epidemiology, and End Results database;85 81,902 women were classified based on the 1988 FIGO staging system compared with the 2009 system. Five-year survival was calculated based on disease grade and whether lymphadenectomy was performed. The authors found survival for stage IA based on the 1988 staging system was 90.7% compared with 88.9% for the 2009 system. The 2009 FIGO staging system is highly prognostic based on this study. Prospective data are currently being collected.

Fertility-Preserving Procedures in the Management of Endometrial Cancer The conservative management of women with atypical endometrial hyperplasia or endometrial cancer who desire future fertility has been controversial. Younger age has been associated with a more favorable prognosis. Multiple reports describe therapeutic success with medroxyprogesterone acetate or megesterol acetate.24,86 A multicenter prospective study of 28 women with endometrial carcinoma and 17 women with atypical endometrial hyperplasia were treated with 600 mg of medroxyprogesterone acetate daily with low-dose aspirin for 26 weeks.87 Response was assessed histologically at 8 and 16 weeks of treatment. Complete response was found in 55% of endometrial carcinomas and 82% of atypical endometrial hyperplasia. During the 3-year follow-up there were 12 pregnancies. Seven normal deliveries were achieved. There was a 47% recurrence rate between 7 and 36 months. One woman died of a synchronous ovarian carcinoma. Before conservative management, MRI to exclude myometrial invasion and pathology review to verify grade I disease should be performed. Although there are no prospective randomized studies and no standard accepted therapy, conservative therapy is an option for a well-informed woman.

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Fertility therapy must follow resolution of the endometrial pathology. The role of hysterectomy and bilateral salpingo-oophorectomy after childbearing is uncertain.

Management of Menopausal Symptoms Estrogen replacement therapy probably has no effect on survival in women with early stage disease. Barakat et al reported a GOG study of 1,236 assessable women entered into a randomized double-blind study of estrogen replacement therapy compared with placebo in women with stage I or II disease. The median follow-up was 35.7 months. The mean age at diagnosis for the 618 women assigned to estrogen therapy was 57 years. The study was halted before completion after the results of the Women’s Health Initiative were made public. Although this study cannot conclusively refute or support the safety of estrogen with regard to risk of recurrence of endometrial cancer, the absolute recurrence rate (2.1%) and the incidence of new malignancy were low.88 Hot flushes can be treated with venlafaxine, clonidine, or progestin therapy. Osteoporosis can be prevented with biphosphosphonates or raloxifene. Weight reduction and lifestyle modification should be encouraged in obese women. Nutritional and exercise counseling should be offered. REFERENCES 1. Siegel R, Naishadham J, Jemal A. Cancer statistics 2012. CA Cancer J Clin 2012;62:10 –29. 2. Sorosky JI. Endometrial cancer. Obstet Gynecol 2008;111: 436 – 47. 3. Prat J, Gallardo A, Cuatrecasas M, Catasus L. Endometrial carcinoma: pathology and genetics. Pathology 2007;39:1–7. 4. Courneya KS, Karvinen KH, Campbell KL, Pearcey RG, Dundas G, Capstick V, et al. Associations among exercise, body weight, and quality of life in a population-based sample of endometrial cancer survivors. Gynecol Oncol 2005;97: 422–30. 5. Anderson B, Connor JP, Andrews JI, Davis CS, Buller RE, Sorosky JI, et al. Obesity and prognosis in endometrial cancer. Am J Obstet Gynecol 1996;174:1171–78. 6. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348: 1625–38. 7. von Gruenigen VE, Tian C, Frasure H, Waggoner S, Keys H, Barakat RR. Treatment effects, disease recurrence, and survival in obese women with early endometrial carcinoma: a Gynecologic Oncology Group study. Cancer 2006;107: 2786 –91. 8. von Gruenigen VE, Waggoner SE, Frasure HE, Kavanagh MB, Janata JW, Rose PG, et al. Lifestyle challenges in endometrial cancer survivorship. Obstet Gynecol 2011;117:93–100. 9. Temkin SM, Pezzullo JC, Hellmann M, Lee YC, Abulafia O. Is body mass index an independent risk factor of survival among patients with endometrial cancer? Am J Clin Oncol 2007;30: 8 –14.

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